Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Medicine and Surgery/Medical Oncology
Universidad Universitat Autònoma Barcelona and Vall d’Hebron Institute of Oncology (VHIO)
Head, Breast Cancer Program
Vall d’Hebrón University Hospital
Cristina Saura, MD, PhD, has disclosed that she has received consulting fees or travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche, Genomic Health, Merck, Novartis, Pfizer, Philips HealthWorks, Pierre Fabre, Puma, Sanofi, Seattle Genetics, and Synthon.
In this commentary, breast cancer expert Cristina Saura, MD, PhD, answers questions on the management of patients with HER2-positive metastatic breast cancer (MBC) posed by the audience during a live CCO Webinar earlier this year.
What percentage of patients receiving standard anti‑HER2 therapy in the neoadjuvant and adjuvant settings go on to develop metastases?
I’ll point to the phase III KATHERINE trial, which enrolled patients with HER2-positive early breast cancer who, despite neoadjuvant taxane therapy plus trastuzumab, were found to have residual invasive disease at surgery. After 14 cycles of either trastuzumab emtansine (T-DM1) or trastuzumab as adjuvant therapy, distant recurrence was evident in 11% vs 16% of patients, respectively, with approximately 5% of these first invasive disease events occurring in the central nervous system (CNS) in each arm. Going forward, the phase III CompassHER2 RD trial (NCT04457596) will assess whether the addition of tucatinib to T-DM1 may better prevent these relapses and the DESTINY-Breast05 trial will compare the efficacy of trastuzumab-deruxtecan vs T-DM1 in that setting.
Why was tucatinib compared with placebo and not lapatinib in HER2CLIMB?
HER2CLIMB is an international, randomized, double-blind phase II trial comparing tucatinib with placebo in the context of a trastuzumab plus capecitabine backbone for patients with previously treated HER2-positive MBC, including those with brain metastases.
Data from the phase III GBG 26/BIG 3-05 trial showed that trastuzumab plus capecitabine prolonged time to progression and improved overall response in trastuzumab-pretreated patients compared with capecitabine alone. Furthermore, the phase III CEREBEL trial (stopped early for futility) demonstrated longer PFS and OS among patients treated with trastuzumab plus capecitabine vs lapatinib plus capecitabine.
Although limited retrospective data exist for the combination of lapatinib with trastuzumab plus capecitabine, there remains a lack of published randomized clinical trials. Thus, in designing a reference arm for HER2CLIMB, investigators chose the designated doublet, not a lapatinib-containing triplet. It is conceivable that the observed difference in benefit for HER2CLIMB could have been lower if they had compared tucatinib against lapatinib with both TKIs in combination with trastuzumab plus capecitabine, but we currently do not have that answer.
How do we manage patients who received pertuzumab and T-DM1 for early‑stage breast cancer? Does this patient history change the recommended treatment paradigm for metastatic disease?
This is an open question for our clinical practice. The key determining factor is time since the end of last treatment. Based on what was done with the phase III CLEOPATRA trial, I would consider treatment with pertuzumab plus trastuzumab and a taxane for patients relapsing more than 12 months after finishing treatment for early stage disease. However, if relapse occurred within 12 months—especially within 6 months—I would start treatment directly with T-DM1 in those patients who had not previously been treated with this agent.
For patients like those from the KATHERINE trial where they’ve received dual blockade plus T-DM1 in the early disease setting, choice of therapy at progression to MBC is even more complicated and based on scant data. Here again, if the relapse occurs more than 12 months after finishing treatment for early-stage disease, I would consider treatment with pertuzumab plus trastuzumab and a taxane. However, for those patients who relapse within 12 months, I would consider the newer therapies including trastuzumab deruxtecan and tucatinib with trastuzumab plus capecitabine if available or on a clinical trial.
Is there any future role for immunotherapy among patients with HER2‑positive MBC?
Where there has been notable success utilizing anti-HER2 monoclonal antibodies, antibody–drug conjugates, and TKIs for HER2-positive MBC, other immunotherapy approaches such as checkpoint inhibition have yielded mixed results across small early-stage trials.
Among encouraging preliminary data are those from the phase Ib/II PANACEA trial, which showed activity of pembrolizumab in combination with trastuzumab, the phase Ib JAVELIN trial, which showed activity of anti–PD-L1 avelumab, and the phase II KATE-2 trial where atezolizumab added to T-DM1 did not significantly increase PFS or OS in the ITT population but both were numerically longer in PD-L1 positive patients receiving the combination. It is hoped that by identifying markers (eg, high PD-L1 expression) that correlate with efficacy, we can target these developing treatment options to patient populations where they may exert their greatest effects while reducing potential toxicity exposure among patients who are less likely to experience clinical benefit.
What questions do you have about recent developments in the care of patients with HER2-positive MBC? Please join the conversation by leaving a comment.
Click here to use CCO’s “Interactive Decision Support Tool: Expert Guidance on Selecting Treatment for HER2-Positive Metastatic Breast Cancer” to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations.
For easy access to this and several other patient management tools from CCO, download the CCO Decision Support app from the app store on your phone!